Novel Phosphonate and Phosphonic Acid RAFT Agents and Monomers, Along with Methods of Their Manufacture and Use

ABSTRACT

An intermediate compound for forming a RAFT agent is provided that can have the formula: 
     
       
         
         
             
             
         
       
     
     where n is an integer from 1 to 20; m is an integer from 0 to 20; R 1  is H, an alkyl group, or a cyano group; R 2  is H, an alkyl group, or a cyano group; Y is OH, COOH, or NH 2 ; and X is OH, COOH, NH 2 , a nitrobenzyl, benzyl, or para-methyl benzyl group. A RAFT agent is also provided that comprises a thiocarbonylthio-containing organic compound having a phosphonic end group. A method is also provided for forming a polymer chain on a surface of a nanoparticle utilizing the RAFT agent, along with nanoparticles and nanocomposites formed therefrom.

PRIORITY INFORMATION

The present application claims priority to U.S. Provisional PatentApplication Ser. No. 61/877,027 titled “Novel Phosphonate and PhosphonicAcid RAFT Agents and Monomers, Along with Methods of Their Manufactureand Use” of Benicewicz, et al. filed on Sep. 12, 2013, the disclosure ofwhich is incorporated by reference herein.

FIELD OF THE INVENTION

Novel RAFT agents and monomers are generally provided, along with theirmethods of manufacture and use.

BACKGROUND

Polymer coated nanomaterials are useful in many applications, includingin LEDs and bioimaging systems. However, the commercial usage ofnanomaterials is limited by the poor optical and mechanical propertiesof the composite when the nanomaterial and polymer are blended together,which typically results in opaque films that have poor mechanicalproperties and are filled with aggregates (clumps of nanomaterials). Forexample, in LED device applications, high refractive index nanomaterialsare in high demand as they would allow more light to be emitted with thesame power input.

Nanomaterial functionalization is an exquisite process where particleshave to be covered with polymers uniformly and via an easy process forany usage. This process provides a simple and versatile method tofunctionalize different nanomaterials including clays, alumina, TiO₂,CdSe etc. This process provides several methods of achieving polymerfunctionalization, including grafting-to, grafting-from andgrafting-through techniques. Additionally, this process eliminatesseveral expensive steps that are currently in use, which wouldfacilitate mass production of such nanocomposites for opticalapplications. Typically, commercial nanocomposites have refractiveindexes (RIs) from 1.3-1.5.

As such, a need exists for highly transparent and robust nanocompositesusing polymers with special anchor points that bind extremely well withthe nanomaterial.

SUMMARY

Objects and advantages of the invention will be set forth in part in thefollowing description, or may be obvious from the description, or may belearned through practice of the invention.

An intermediate compound is, in one embodiment, generally provided forforming a RAFT agent. The intermediate compound can have the formula:

where n is an integer from 1 to 20 (e.g., 2 to 10); m is an integer from0 to 20 (e.g., 2 to 10); R₁ is H, an alkyl group, or a cyano group; R₂is H, an alkyl group, or a cyano group; Y is OH, COOH, or NH₂; and X isOH, COOH, NH₂, a nitrobenzyl, benzyl, or para-methyl benzyl group. Saltsof such intermediate compounds are also generally provided.

A RAFT agent is, in one embodiment, generally provided that comprises athiocarbonylthio-containing organic compound having a phosphonic endgroup. For example, the RAFT agent can have the formula:

where Z is an organic linkage; R₁ is H or an alkyl group; R₂ is H or analkyl group; A is O, S, or NH; and R″ is an organic end group. Forinstance, R″ can comprise an alkyl group terminating with a phenyl endgroup or a nitrophenyl end group, and/or may comprise a benzyl group, anitrobenzyl group, or a para-methyl benzyl group. In one particularembodiment, the RAFT agent can have the formula:

where n is 1 to 10 (e.g., 1-6), m is 1 to 10 (e.g., 1 to 6), R₁ is H oran alkyl group; R₂ is H or an alkyl group; A is O, S, or NH; and R″ isan organic end group. Salts of the RAFT agents are also generallyprovided.

A method is also generally provided for forming a polymer chain on asurface of a nanoparticle. In one embodiment, the method can include:attaching a RAFT agent disclosed herein to the surface of thenanoparticle such that the phosphonic group of the RAFT agent iscovalently bonded to the surface of the nanoparticle; and attaching apolymer to the RAFT agent (e.g., via a grafting-to method or agrafting-from method).

A nanocomposite is also generally provided that, in one embodiment,comprises a nanoparticle defining a surface, a RAFT agent attached tothe surface of the nanoparticle, and a polymer attached to the RAFTagent. Generally, the RAFT agent comprises a thiocarbonylthio-containingorganic compound having a phosphonic end group (such as discussed above)that is covalently bonded to the surface of the nanoparticle.

Other features and aspects of the present invention are discussed ingreater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

A full and enabling disclosure of the present invention, including thebest mode thereof to one skilled in the art, is set forth moreparticularly in the remainder of the specification, which includesreference to the accompanying figures, in which:

FIG. 1 shows an exemplary nanocomposite according to one particularembodiment of the present invention; and

FIG. 2 shows a close-up view of the nanocomposite to show the attachmentbetween the surface of the nanoparticle and the polymer via the RAFTagent, according to one particular embodiment of the present invention.

Repeat use of reference characters in the present specification anddrawings is intended to represent the same or analogous features orelements of the present invention.

DEFINITIONS

Chemical elements are discussed in the present disclosure using theircommon chemical abbreviation, such as commonly found on a periodic tableof elements. For example, hydrogen is represented by its common chemicalabbreviation H; helium is represented by its common chemicalabbreviation He; and so forth.

As used herein, the prefix “nano” refers to the nanometer scale (e.g.,from about 1 nm to about 999 nm). For example, particles having anaverage diameter on the nanometer scale (e.g., from about 1 nm to about999 nm) are referred to as “nanoparticles”. Particles having an averagediameter of greater than 1,000 nm (i.e., 1 μm) are generally referred toas “microparticles”, since the micrometer scale generally involves thosematerials having an average size of greater than 1 μm.

As used herein, the term “polymer” generally includes, but is notlimited to, homopolymers; copolymers, such as, for example, block,graft, random and alternating copolymers; and terpolymers; and blendsand modifications thereof. Furthermore, unless otherwise specificallylimited, the term “polymer” shall include all possible geometricalconfigurations of the material. These configurations include, but arenot limited to isotactic, syndiotactic, and random symmetries.

The term “organic” is used herein to refer to a class of chemicalcompounds that are comprised of carbon atoms. For example, an “organicpolymer” is a polymer that includes carbon atoms in the polymerbackbone, but may also include other atoms either in the polymerbackbone and/or in side chains extending from the polymer backbone(e.g., oxygen, nitrogen, sulfur, etc.).

The polydispersity index (PDI) is a measure of the distribution ofmolecular mass in a given polymer sample. The PDI calculated is theweight average molecular weight divided by the number average molecularweight. It indicates the distribution of individual molecular masses ina batch of polymers. The PDI has a value equal to or greater than 1, butas the polymer chains approach uniform chain length, the PDI approachesunity (i.e., 1).

DETAILED DESCRIPTION

Reference now will be made to the embodiments of the invention, one ormore examples of which are set forth below. Each example is provided byway of an explanation of the invention, not as a limitation of theinvention. In fact, it will be apparent to those skilled in the art thatvarious modifications and variations can be made in the inventionwithout departing from the scope or spirit of the invention. Forinstance, features illustrated or described as one embodiment can beused on another embodiment to yield still a further embodiment. Thus, itis intended that the present invention cover such modifications andvariations as come within the scope of the appended claims and theirequivalents. It is to be understood by one of ordinary skill in the artthat the present discussion is a description of exemplary embodimentsonly, and is not intended as limiting the broader aspects of the presentinvention, which broader aspects are embodied exemplary constructions.

Generally speaking, novel RAFT agents are presently disclosed that haveunique synthetic routes and polymers with novel binding points toinorganic materials. In particular embodiments, the RAFT agents areprovided that include a phosphonate or phosphonic acid functional groupthat can attach to various inorganic materials to get high refractiveindex polymers. The novel RAFT agents outlined herein facilitate thedevelopment of polymers with phosphonic acid/phosphate end groups thatcan be used to attach with a variety of nanomaterials.

I. RAFT Polymerization

Reversible Addition-Fragmentation chain Transfer (RAFT) polymerizationis one type of controlled radical polymerization. RAFT polymerizationuses thiocarbonylthio compounds, such as dithioesters, dithiocarbamates,trithiocarbonates, and xanthates, in order to mediate the polymerizationvia a reversible chain-transfer process. RAFT polymerization can beperformed by simply adding a chosen quantity of appropriate RAFT agents(thiocarbonylthio compounds) to a conventional free radicalpolymerization. RAFT polymerization is particularly useful with monomershaving a vinyl functional group (e.g., a (meth)acrylate group).

Typically, a RAFT polymerization system includes the monomer, aninitiator, and a RAFT agent (also referred to as a chain transferagent). Because of the low concentration of the RAFT agent in thesystem, the concentration of the initiator is usually lower than inconventional radical polymerization. Suitable radical initiators can beazobisisobutyronitrile (AIBN), 4,4′-azobis(4-cyanovaleric acid) (ACVA),etc.

RAFT agents are generally thiocarbonylthio compounds, such as generallyshown below:

where the z group primarily stabilizes radical species added to the C═Sbond and the R group is a good homolytic leaving group which is able toinitiate monomers. The z and R″ group of a RAFT agent is chosenaccording to a number of considerations. The z group primarily affectsthe stability of the S═C bond and the stability of the adduct radical(polymer-S—C.(Z)—S-polymer), which, in turn, affect the position of andrates of the elementary reactions in the pre- and main-equilibrium. TheR″ group stabilizes a radical such that the right hand side of thepre-equilibrium is favored, but remains unstable enough that it canreinitiate growth of a new polymer chain.

As stated, RAFT is a type of living polymerization involving aconventional radical polymerization in the presence of a reversiblechain transfer reagent. Like other living radical polymerizations, thereis minimized termination step in the RAFT process. The reaction isstarted by radical initiators (e.g., AIBN). In this initiation step, theinitiator reacts with a monomer unit to create a radical species whichstarts an active polymerizing chain. Then, the active chain reacts withthe thiocarbonylthio compound, which kicks out the homolytic leavinggroup (R″). This is a reversible step, with an intermediate speciescapable of losing either the leaving group (R″) or the active species.The leaving group radical then reacts with another monomer species,starting another active polymer chain. This active chain is then able togo through the addition-fragmentation or equilibration steps. Theequilibration keeps the majority of the active propagating species intothe dormant thiocarbonyl compound, limiting the possibility of chaintermination. Thus, active polymer chains are in equilibrium between theactive and dormant species. While one polymer chain is in the dormantstage (bound to the thiocarbonyl compound), the other is active inpolymerization.

By controlling the concentration of initiator and thiocarbonylthiocompound and/or the ratio of monomer to thiocarbonylthio compound, themolecular weight of the polymeric chains can be controlled with lowpolydispersities.

Depending on the target molecular weight of final polymers, the monomerto RAFT agent ratios can range from about 10 to about 10,000 inparticular embodiments. Other reaction parameters can be varied tocontrol the molecular weight of the final polymers, such as solventselection, reaction temperature, and reaction time. For instance,solvents can include conventional organic solvents such astetrahydrofuran, toluene, dimethylformamide, anisole, acetonitrile,dichloromethane, etc. The reaction temperature can range from roomtemperature (e.g., about 20° C.) to about 120° C. The reaction time canbe from less than about 1 h to about 48 h.

The RAFT process allows the synthesis of polymers with specificmacromolecular architectures such as block, gradient, statistical,comb/brush, star, hyperbranched, and network copolymers.

Because RAFT polymerization is a form of living radical polymerization,it is ideal for synthesis of block copolymers. For example, in thecopolymerization of two monomers (A and B) allowing A to polymerize viaRAFT will exhaust the monomer in solution with significantly suppressedtermination. After monomer A is fully reacted, the addition of monomer Bwill result in a block copolymer. One requirement for maintaining anarrow polydispersity in this type of copolymer is to have a chaintransfer agent with a high transfer constant to the subsequent monomer(monomer B in the example).

II. Novel RAFT Agents

In order to synthesize phosphonic acid functionalized polymers, RAFTagents are provided that generally include a thiocarbonylthio-containingorganic compound having a phosphonic end group. The phosphonic end groupgenerally serves as an end group on the “z” group in the RAFT agent.While phosphonic acid end groups can be present on either the z or R″group, the following examples are focused on a phosphonic acid end grouppresent as part of the z group. In one embodiment, the RAFT agent can begenerally represented by the formula:

where Z is an organic linkage (with Z and the phosphonate group formingthe z group discussed above); R₁ is H or an alkyl group (e.g., having aformula of C_(n)H_(2n+1), with n being an integer of 1 to 6, such as 1to 4); R₂ is H or an alkyl group (e.g., having a formula ofC_(n)H_(2n+1), with n being an integer of 1 to 6, such as 1 to 4); A isO, S, or NH; and R″ is an organic end group that configured to cleaveduring the RAFT process and reinitiate the polymerization. In oneparticular embodiment, R″ is an organic end group configured to affectthe stability of the S═C bond and the stability of the adduct radical(polymer-S—C.(Z)—S-polymer). As such, the R″ can be varied by changingthe chemical composition of the organic group, and can be used to tailorthe polydispersity of the resulting polymer. By changing theelectron-donating or withdrawing nature of the R″ group, thepolydispersity can be tuned for the desired need in the application. Thepolydispersity can influence the mixing of the polymer-modifiednanomaterial with the matrix polymer, and can have a significant effecton its physical and surface properties. In particular embodiments, R″includes a nitrobenzyl, benzyl, or para-methyl benzyl end group (eitherbonded directly to the thiocarbonyl group or via an alkyl group). Assuch, R″ can, in one embodiment, include an alkyl group terminating witha nitrobenzyl, benzyl, or para-methyl benzyl end group.

Particularly suitable alkyl groups that can form R₁ and/or R₂ includemethyl (CH₃), ethyl (CH₂CH₃), propyl (CH₂CH₂CH₃), iso-propyl (CH(CH₃)₂);butyl (e.g., CH₂CH₂CH₂CH₃), or tert-butyl (C(CH₃)₃).

In one embodiment, an ester group is included in the organic linkage ofZ. For example, the organic linkage of Z can be an ethyl acetatelinkage, which can be generally represented by the formula:

where n is 1 to 10 (e.g., 1-6), m is 1 to 10 (e.g., 1 to 6), R₁ is H oran alkyl group; R₂ is H or an alkyl group; A is O, S, or NH; and R″ isan organic end group.

In particular embodiments, a phenyl group (serving as the z group in theRAFT agent) may be oppositely positioned from the phosphonic end groupwith the thiocarbonylthio group positioned between. The phenyl groupmay, in one particular embodiment, have an electron withdrawing group onits ring (e.g., at the para position), which can help controlpolymerization and, in turn, can lead to lower polydispersity of theresulting polymer. For example, a nitro functional group (—NO₂) can bepositioned thereon (e.g., bonded to the phenyl ring at the paraposition).

A. Exemplary RAFT Agents

Particularly suitable RAFT agents for synthesizing phosphonic acidfunctionalized polymers have the formulas:

B. Intermediate Compounds

The RAFT agents described can be, in particular embodiments, formed fromintermediate compounds such as the ones described below. In oneembodiment, the intermediate compound has the formula:

where n is an integer from 1 to 20 (e.g., about 2 to about 10); m is aninteger from 0 to 20 (e.g., about 0 to about 10); R₁ is H, an alkylgroup, or a cyano group; R₂ is H, an alkyl group, or a cyano group; Y isOH, COOH, or NH₂; and X is OH, COOH, NH₂, a nitrobenzyl, benzyl, orpara-methyl benzyl group. In particular embodiments, the constituentsR₁, R₂, and/or X and the value of n and m in the intermediate compoundcan translate, respectively, into the constituents R₁, R₂, and/or R″ andthe values of n and m of Formula 3.

Particularly suitable intermediate compounds can include, for example,compounds having the formulas:

III. Nanoparticles

The presently disclosed methods can be utilized on a variety ofdifferent types of nanoparticles. The nanoparticle may comprise, forexample, natural or synthetic nanoclays (including those made fromamorphous or structured clays), inorganic metal oxides (e.g., silica,alumina, and the like), nanolatexes, organic nanoparticles, etc.Particularly suitable nanoparticles include inorganic nanoparticles,such as silica, alumina, titania (TiO₂), indium tin oxide (ITO), CdSe,etc., or mixtures thereof. Suitable organic nanoparticles includepolymer nanoparticles, carbon, graphite, graphene, carbon nanotubes,virus nanoparticles, etc., or mixtures thereof.

Nanoparticles as used herein means particles (including but not limitedto rod-shaped particles, disc-shaped particles, platelet-shapedparticles, tetrahedral-shaped particles), fibers, nanotubes, or anyother materials having at least one dimension on the nano scale. In oneembodiment, the nanoparticles have an average particle size of about 1to about 1000 nanometers, preferably 2 to about 750 nanometers. That is,the nanoparticles have a dimension (e.g., a diameter or length) of about1 to 1000 nm. Nanotubes can include structures up to 1 centimeter long,alternatively with a particle size from about 2 to about 50 nanometers.Due to their size, nanoparticles have very high surface-to-volumeratios.

The nanoparticles may be crystalline or amorphous. A single type ofnanoparticle may be used, or mixtures of different types ofnanoparticles may be used. If a mixture of nanoparticles is used theymay be homogeneously or non-homogeneously distributed in the compositematerial or a system or composition containing the composite material.Non-limiting examples of suitable particle size distributions ofnanoparticles are those within the range of about 2 nm to less thanabout 750 nm, alternatively from about 2 nm to less than about 200 nm,and alternatively from about 2 nm to less than about 150 nm.

It should also be understood that certain particle size distributionsmay be useful to provide certain benefits, and other ranges of particlesize distributions may be useful to provide other benefits (forinstance, color enhancement requires a different particle size rangethan the other properties). The average particle size of a batch ofnanoparticles may differ from the particle size distribution of thosenanoparticles. For example, a layered synthetic silicate can have anaverage particle size of about 25 nanometers while its particle sizedistribution can generally vary between about 10 nm to about 40 nm.

In one embodiment, the nanoparticles can be exfoliated from a startingmaterial to form the nanoparticles. Such starting material may have anaverage size of up to about 50 microns (50,000 nanometers). In anotherembodiment, the nanoparticles can be grown to the desired averageparticle size.

IV. Attaching a Polymer to the Nanoparticle

The RAFT agents (discussed in section II above) are attached to thesurface of the nanoparticle (discussed in section III above) forsubsequent attachment/formation of a polymeric chain thereto (e.g., viaa “grafting-to” or “grafting-from” approach, as described in greaterdetail below). That is, the RAFT agent can be covalently bonded directlyto the surface of the nanoparticle via its phosphonate group.

Two methods can be utilized to form the polymeric chain extending fromthe nanoparticles via the attached RAFT agent: a “grafting-from”approach and a “grafting-to” approach. These strategies are explained inmore details in the following sections. (See also, U.S. Publication No.2013/0041112 of Benicewicz, et al.; U.S. Publication No. 2012/0302700 ofTao, et al.; and international patent application publication no.WO/2013/078309 of Benicewicz, et al., the disclosures of which areincorporated by reference herein.)

A. “Grafting-from” Methods

In one embodiment, the polymeric chain can be formed by RAFTpolymerization of a plurality of monomers on the attached RAFT agent,resulting in the polymeric chain being covalently bonded to thenanoparticle via the RAFT agent. The particular types of monomer(s)and/or RAFT polymerization conditions can be selected based upon thedesired polymeric chain to be formed. For example, monomers containingacrylate, methacrylate groups, acrylamides, styrenics, etc., areparticularly suitable for formation of the polymeric chain.

Thus, the “grafting-from” method involves formation of the polymericchain onto the attached RAFT agent and results in the polymeric chainbeing covalently bonded to the nanoparticle via the attached RAFT agent.

B. “Grafting-To” Methods

In one embodiment, the polymeric chain can be first polymerized via RAFTpolymerization with the RAFT agent of section II above and subsequentlycovalently bonded directly to the surface of the nanoparticle, via itsphosphonate end group. Thus, in this embodiment, the polymeric chain hasbeen polymerized prior to attachment to the nanoparticle's surface.

Alternatively, the polymeric chain can be first polymerized andsubsequently covalently bonded to the surface of the nanoparticle, via aRAFT agent of section II attached directly to the surface of thenanoparticle. Thus, in this embodiment, the first polymeric chain hasbeen polymerized prior to attachment to the first anchoring compound. Inthis embodiment, the first polymeric chain is not limited to the type ofpolymerization and/or types of monomer(s) capable of being polymerizeddirectly to the attached RAFT agent. As such, as long as the polymericchain defines a functional group that can react and bond to the attachedRAFT agent, any polymeric chain can be bonded to the nanoparticle.

V. Nanocomposites

Through these methods, nanocomposites can be formed having a polymerchain attached to the surface of a nanoparticle (of section III above)via a phosphonate/phosphonic acid group of a RAFT agent (as in sectionII above). FIG. 1 shows an exemplary nanocomposite 10 that includes ananoparticle 12 defining a surface 11. A RAFT agent 14 is attacheddirectly to the surface 11 via a covalent bond 13. A polymer 16 isattached to RAFT agent 14. As shown, multiple RAFT agents 14 andpolymers 16 can be attached to the nanoparticle 12 to form thenanocomposite 10.

For example, as shown in the close-up view of FIG. 2, the phosphonategroup 15 of the RAFT agent 14 can be covalently bonded to the surface 11of the nanoparticle 12, while the polymer chain 16 can be covalentlybonded to the thiocarbonyl group 17 of the RAFT agent 14.

In one particular embodiment, a nanocomposite can be formed from TiO₂nanoparticles to increase their refractive index. The refractive index(RI) of TiO₂ ranges from 2.4-2.6. However, with the incorporation ofpolymers with phosphonic acids to TiO₂ nanoparticles, higher RInanocomposites can be obtained, such as up to 1.8 (e.g., about 1.2 toabout 1.8, such as about 1.5 to about 1.8).

Examples

In order to synthesize phosphonic acid functionalized polymers, RAFTagents were designed using a carboxylic acid functionalized thiol. Afterthe thiol is reacted with carbon disulfide to form a trithiocarbonate,the carboxylic acid end can be utilized to react with a hydroxyphosphonate. The resulting novel phosphonate trithiocarbonate can bedeprotected to the phosphonic acid trithiocarbonate to graft directly toTiO₂ nanoparticles for the ‘grafting-from’ technique. Alternatively, thephosphonate trithiocarbonate can be polymerized with a variety ofmonomers to get phosphonate functionalized polymers. These polymers canbe deprotected to get the phosphonic acid polymer for the ‘grafting-to’technique.

Furthermore, an alternative approach for the purpose of multiplephosphonic acid binding sites was to use phosphonic acid based monomers.Methacrylate based phosphonate monomers were synthesized using thehydroxy phosphonate and methacryloyl chloride. Such polymers with themultiple binding sites were attached with TiO₂ to form novelnanocomposite systems.

Experimental: Section 1

Dithiodipropionic acid (2.38 mmol) was added to a round bottom flaskwith DCM (10 mL) and THF (5 mL). Diethyl hydroxyl phosphate (6.66 mmol)was added to the solution followed by DMAP (2.38 mmol). In a separatevial DCC (6.90 mmol) was dissolved in THF (2 mL). The DCC solution wasadded drop-wise under stirring in an ice bath. The mixture was flushedwith Nitrogen and stirred at ambient temperature for 28 hours.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.35 (t, 3H), 2.8 (t, 2H),2.9 (t, 2H), 4.1-4.3 (q, 2H), 4.4 (d, 2H)

¹³C NMR: 16 (CH₃—CH₂), 32 (COOH—CH₂—CH₂), 34 (COOH—CH₂—CH₂), 62(CH₃—CH₂), 171 (COOH—CH₂—CH₂)

Experimental: Section 2

Diethyl Ether (10 mL) and TEA (2.77 mL, 19.88 mmol) were added to around bottom flask. 3-mercaptopropionic acid (9.42 mmol) was addeddrop-wise under stirring in an ice bath. Carbon Disulfide (0.87 mL,14.42 mmol) was added drop-wise under stirring in an ice bath. Solutionwas kept under ice for one hour then ambient temperature for anotherhour. The solvent was then removed by filtration and washed 3 times withdiethyl ether to eliminate excess TEA and Carbon Disulfide.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.2 (TEA), 2.5 (t, 2H), 2.7(t, 2H), 2.9 (TEA).

A suspension was made in diethyl ether. Solid Iodine (0.21 mmol) wasadded in portions and the mixture stirred for 1 hour at roomtemperature. Sodium Iodide was removed by filtration. The yellow brownfiltrate was washed with aqueous sodium thiosulfate and dried overanhydrous sodium sulfate.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.9 (t, 2H), 3.1 (t, 2H).

Experimental: Section 3

3-mercaptopropionic acid (9.42 mmol) added drop-wise to potassiumhydroxide solution in water. Aliquat 336 and Carbon Disulfide mixture(0.57 mL, 9.42 mmol) was added. Solution stirred for 30 minutes atambient temperature. The solution was cooled to −5° C. in a salt watersolution. 4-Toluenesulfonyl chloride (TsCI) (4.71 mmol) was added insmall portions over 5 minutes and stirred at ambient temperature for onehour. The solution was then heated to 45° C. and stirred for 10 minutes.Product was washed with water and recrystallized with acetone.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.8 (t, 2H), 2.95 (t, 2H).

¹³C NMR (75 MHz, CDCl₃), δ (ppm form TMS): 33 (COOH—CH₂—CH₂), 34(COOH—CH₂—CH₂).

Mass: Major peak at 228.

Experimental: Section 4

3-mercaptopropionic acid (9.42 mmol) was mixed with dichloromethane(DCM) (10.2 mL) and the solution was stirred for 10 minutes at ambienttemperature. Triethylamine (TEA) (1.31 mL, 9.42 mmol) was added thencarbon disulfide (0.76 mL, 12.62 mmol) was added drop-wise understirring in an ice bath. The solution was stirred for 5 hours at ambienttemperature. Solvent was partially evaporated under vacuum. Productprecipitated in ether three times and the orange oil was separated fromether by evaporation under vacuum.

Nitrobenzylbromide (9.42 mmol) was dissolved in DCM (1.6 mL). Solutionwas stirred with 3-proprionicacidtrithiocarbonate salt for 16 hours atambient temperature. Nitrobenzylbromide was filtered off and washed withDCM (5 mL). The product was purified by extraction with water and washedtwice with 5 mL of 1M HCl in 95 mL water. The organic phase was driedwith anhydrous sodium sulfate. The solvent was evaporated and yellow oilpurified by a silica gel column (Hexanes/Ethyl acetate).

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.8 (t, 2H), 3.6 (t, 2H), 4.7(s, 2H), 7.5 (d, 2H), 8.15 (d, 2H).

¹³C NMR (75 MHz, CDCl₃), δ (ppm form TMS): 32 (COOH—CH₂—CH₂), 38(COOH—CH₂—CH₂), 48 (CH₂—C—CH—CH—C—NO₂), 124 (CH₂—C—CH—CH—C—NO₂),13O(CH₂—C—CH—CH—C—NO₂), 143 (CH₂—C—CH—CH—C—NO₂), 146(CH₂—C—CH—CH—C—NO₂), 176 (COOH—CH₂—CH₂)

Mass: Major peak at 317.

Experimental: Section 5

Ethyl Disulfide diethyl phosphate (0.39 mmol) and water were dissolvedin dimethylformamide (DMF) (3 mL) in a round bottom flask. The mixturewas flushed with Nitrogen and Tributyl Phosphine (0.132 mL, 0.78 mmol)was added under Nitrogen. The solution was stirred for 1 hour at ambienttemperature. DCM (10 mL) was added and the solution washed with water 3times. The organic layer was rinsed with Sodium Sulfate and evaporationunder vacuum.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.2-1.8 (t, 6H), 2.8 (t, 2H),3.65 (t, 2H), 4.2-4.3 (d, 4H).

Experimental: Section 6

3-mercaptopropionic acid (9.42 mmol) was mixed with DCM (10.25 mL) andthe solution was stirred for 10 minutes at ambient temperature. TEA(1.31 mL, 9.42d mmol) was added then Carbon Disulfide (0.76 mL, 12.62mmol) was added drop-wise under stirring in an ice bath. The solutionwas stirred for 5 hours at ambient temperature. Solvent was partiallyevaporated under vacuum. Product precipitated in ether three times andthe orange oil was separated from ether by evaporation under vacuum.

3-((((1-((6-hydroxyhexyl)oxy)-2-methyl-1-oxopropan-2-yl)thio)carbonothioyl)thio)propanoicacid (9.42 mmol) was dissolved in DCM (1.6 mL). Solution was stirredwith 3-proprionicacidtrithiocarbonate salt for 16 hours at ambienttemperature. Bromide was filtered off and washed with DCM (5 mL). Theproduct was purified by extraction with water and washed twice with 5 mLof 1M HCl in 95 mL water. The organic phase was dried with anhydrousSodium Sulfate. The solvent was evaporated and the yellow oil waspurified by a silica gel column (Hexanes/Ethyl acetate).

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.4-2.1 (m, 8H) 1.6 (s, 6H),2.8 (t, 2H), 3.6 (t, 2H), 3.65 (t, 2H), 4.2 (t, 2H)

¹³C NMR (75 MHz, CDCl₃), δ (ppm form TMS): 24.2 (S—CCH₃CH₃—COOH), 24.3(S—CCH₃CH₃—COOH), 24.8 (CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—OH), 24.9(CH₂—CH₂—CH₂—CH₂—CH₂—CH₂-0H), 27 (CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—OH), 31.5(CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—OH), 32 (COOH—CH₂—CH₂), 35 (COOH—CH₂—CH₂), 52(S—CCH₃CH₃—COOH), 62 (CH₂—CH₂—CH₂—CH₂—CH₂—CH₂-0H), 65(CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—OH)

Mass: Major peak at 167

Experimental: Section 7

Potassium tert-butoxide (KOtBu) (9.42 mmol) and tetrahydrofuran (THF)(15 mL) were stirred for 30 minutes at ambient temperature.3-mercaptopropionic acid (9.42 mmol) was added drop-wise under stirringin an ice bath. The solution was stirred for 30 minutes at ambienttemperature. Carbon disulfide (0.336 mL, 9.73 mmol) was added drop-wiseunder stirring in an ice bath. The solution was stirred for 4 hours atambient temperature. The solution was cooled to 15° C. and solid iodine(9.8 mmol) was added in small portions over 40 minutes. The mixture wasstirred overnight and then filtered. The organic phase was washed withbrine, sodium thiosulfate and followed with brine. The organic layer wasdried with anhydrous Sodium Sulfate.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.8 (t, 2H), 2.55 (t, 2H).

¹³C NMR (75 MHz, CDCl₃), δ (ppm form TMS): 32 (CS—CH₂—CH₂—COOH), 33(CS—CH₂—CH₂—COOH), 175 (CS—CH₂—CH₂—COOH), 207 (CS—CH₂—CH₂—COOH)

Experimental: Section 8

3-mercaptopropionic acid (9.42 mmol) was mixed with DCM (10.2 mL) andthe solution was stirred for 10 minutes at ambient temperature. TEA(1.31 mL, 9.42 mmol) was added, then carbon disulfide (0.76 mL, 12.62mmol) was added drop-wise under stirring in an ice bath. The solutionwas stirred for 5 hours at ambient temperature. Solvent was partiallyevaporated under vacuum. Product precipitated in ether three times andthe orange oil was separated from ether by rotary evaporation.

2-Bromoisobutyrophenone (0.19 mL, 1.13 mmol) was dissolved in chloroform(2 mL) and 3-propioicacidtrithiocarbonate salt (0.36 mL, 1.35 mmol) for16 hours at 60° C. The bromide was filtered off and washed with DCM. Theproduct was purified by extraction twice with water. The organic phasewas dried with anhydrous sodium sulfate and the solvent was evaporated.Final yellow oil was purified by a silica gel column (Hexanes/Ethylacetate).

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.6 (s, 3H), 2.0 (s, 3H), 2.6(t, 2H), 2H), 7.3-7.6 (m, 3H), 8.0-8.2 (d, 2H)

Experimental: Section 9

3-mercaptopropionic acid (9.42 mmol) was mixed with DCM (10.2 mL) andthe solution was stirred for 10 minutes at ambient temperature. TEA(1.31 mL, 9.42 mmol) was added then carbon disulfide (0.76 mL, 12.62mmol) was added drop-wise under stirring in an ice bath. The solutionwas stirred for 5 hours at ambient temperature. Solvent was partiallyevaporated under vacuum. Product precipitated in ether three times andthe orange oil was separated from ether by evaporation under vacuum.

Benzyl bromide (0.347 mL, 2.92 mmol) was dissolved in DCM (3 mL) andstirred with 3-propionic acid trithiocarbonate salt (0.929 mL, 3.51mmol) for 16 hours at ambient temperature. The bromide was filtered offand washed with DCM. The product was purified by extraction twice withwater. The organic phase was dried with anhydrous sodium sulfate and thesolvent was evaporated. The final yellow oil was purified with a silicagel column.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.8 (t, 2H), 3.6 (t, 2H), 4.6(s, 2H), 7.2-7.4 (m, 5H)

Experimental: Section 10

3-mercaptopropionic acid (9.42 mmol) was mixed with DCM (10.2 mL) andthe solution was stirred for 10 minutes at ambient temperature. TEA(1.31 mL, 9.42 mmol) was added then Carbon Disulfide (0.76 mL, 12.62mmol) was added drop-wise under stirring in an ice bath. The solutionwas stirred for 5 hours at ambient temperature. Solvent was partiallyevaporated under vacuum. Product precipitated in ether three times andthe orange oil was separated from ether by evaporation under vacuum.

Benzyl bromide (0.347 mL, 2.92 mmol) was dissolved in DCM (5 mL) andstirred with 3-propionic acid trithiocarbonate salt (0.36 mL, 1.35 mmol)for 16 hours at 60° C. attached to a condenser. The bromide was filteredoff and washed with DCM. The product was purified by extraction twicewith water. The organic phase was dried with anhydrous sodium sulfateand the solvent was evaporated. The final yellow oil was purified with asilica gel column (Hexanes/Ethyl acetate).

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.8 (t, 2H), 3.6 (t, 2H), 4.5(c′, 2H), 4.6 (s, 2H), 7.2-7.4 (m, 5H)

Experimental: Section 11

3-mercaptopropionic acid (9.42 mmol) was mixed with DCM (10.2 mL) andthe solution was stirred for 10 minutes at ambient temperature. TEA(1.31 mL, 9.42 mmol) was added then carbon disulfide (0.76 mL, 12.62mmol) was added drop-wise under stirring in an ice bath. The solutionwas stirred for 5 hours at ambient temperature. Solvent was partiallyevaporated under vacuum. Product precipitated in ether three times andthe orange oil was separated from ether by rotvap.

Alpha-bromo-p-xylene (1.13 mmol) was dissolved in DCM (2 mL) and stirredwith 3-propionic acid trithiocarbonate salt (0.72 mL, 2.71 mmol) for 16hours at 60° C. attached to a condenser. The bromide was filtered offand washed with chloroform. The product was purified by extraction twicewith water. The organic phase was dried with anhydrous sodium sulfateand the solvent was evaporated. The final yellow oil was purified with asilica gel column (Hexanes/Ethyl acetate).

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.3 (s, 3H), 2.8 (t, 2H), 3.6(t, 2H), 4.6 (s, 2H), 7.0-7.2 (d, 4H)

Experimental: Section 12

2-((((4-nitrobenzyl)thio)carbonothioyl)thio)acetic acid (NTCTPA) (0.945mmol) was added to a round bottom flask and dissolved in DCM (10 mL).Diethyl hydroxy phosphate (0.859 mmol) was added followed bydimethylaminopyridine (DMAP) (0.172 mmol). In a separate vialN,N′-Dicyclohexylcarbodiimide (DCC) (0.945 mmol) was dissolved in DCM (2mL). The DCC solution was added drop-wise under stirring in an ice bath.The flask was flushed with nitrogen and stirred for 28 hours at ambienttemperature.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.3 (t, 6H), 2.8 (t, 2H), 3.6(t, 2H), 4.2 (q, 4H), 4.4 (d, 2H), 4.65 (s, 2H), 7.5 (d, 2H), 8.2 (d,2H)

¹³C NMR (75 MHz, CDCl₃), δ (ppm form TMS): 16 (CH₃—CH₂—P), 31(COOH—CH₂—CH₂—S), 33 (COOH—CH₂—CH₂—S), 63 (CH₃—CH₂—P), 67 (P—CH₂—O), 124(S—CH₂—C—CH—CH—C—NO₂), 130 (S—CH₂—C—CH—CH—C—NO₂)

³¹P: 24

Mass: Major peak at 468.

Experimental: Section 13

3-mercaptopropionic acid (18.84 mmol) was mixed with DCM (20.5 mL) andthe solution was stirred for 10 minutes at ambient temperature. Carbondisulfide (1.52 mL, 25.25 mmol) was added drop-wise under stirring in anice bath. The solution was stirred for 5 hours at ambient temperature.Solvent was partially evaporated under vacuum. Product precipitated inether three times and the orange oil was separated from ether bydimethylaminopyridine. Alpha-Bromo-p-xylene (9.42 mmol) was dissolved inchloroform (2 mL) and stirred with 3-propionic acid trithiocarbonatesalt for 16 hours at 60° C. The bromide was filtered off and washed withchloroform. The product was purified by extraction twice with water. Theorganic phase was dried with anhydrous sodium sulfate and the solventwas evaporated. The final yellow oil was purified with a silica gelcolumn.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.3 (s, 3H), 2.8 (t, 2H), 3.6(t, 2H), 4.6 (s, 2H), 7.2-7.3 (d, 2H), 8.1 (d, 2H)

¹³C NMR (75 MHz, CDCl₃), δ (ppm form TMS): 22 (S—CH₂—C—CH—CH—C—CH₃), 31(COOH—CH₂—CH₂—S), 33 (COOH—CH₂—CH₂—S), 41 (S—CH₂—C—CH—CH—C—CH₃), 128(S—CH₂—C—CH—CH—C—CH₃), 129 (S—CH₂—C—CH—CH—C—CH₃), 132(S—CH₂—C—CH—CH—C—CH₃), 138 (S—CH₂—C—CH—CH—C—CH₃), 176 (COOH—CH₂—CH₂—S)

Mass: Major peaks 105, 210 others 55, 76, 91, 137, 286

Experimental: Section 14

(diethoxyphosphoryl)methyl2-((((4-nitrobenzyl)thio)carbonothioyl)thio)acetate (NTCTPA-diethylphosphate) (0.205 mmol) was added to DCM (3 mL). Trimethylsilyl bromide(TMSBr) (0.108 mL, 0.205 mmol) was added to the solution drop-wise undernitrogen in an ice bath. The solution was stirred for 4 hours at ambienttemperature then evaporated under vacuum. Methanol (3 mL) was added andthe solution was stirred for 1 hour. The solution was evaporated undervacuum and recrystallized in 10% DCM/hexane solution.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.8 (t, 2H), 3.6 (t, 2H), 4.4(d, 2H), 4.65 (s, 2H), 7.5 (d, 2H), 8.2 (d, 2H)

³¹P: 19.22

Mass: Major peak: 449

Experimental: Section 15

3-mercaptopropionic acid (4.11 mL, 47.11 mmol) was mixed with DCM (20.5mL) and TEA (6.57 mL, 47.11 mmol) and the solution was stirred for 10minutes at ambient temperature. Carbon disulfide (3.82 mL, 63.12 mmol)was added drop-wise under stirring in an ice bath. The solution wasstirred for 5 hours at ambient temperature. Solvent was partiallyevaporated under vacuum. Product precipitated in ether three times andthe orange oil was separated from ether by evaporated under vacuum.Benzyl bromide (2.88 mL, 23.72 mmol) was dissolved in chloroform (20.5mL) and stirred with 3-propionic acid trithiocarbonate salt for 16 hoursat 60° C. The bromide was filtered off and washed with chloroform. Theproduct was purified by extraction twice with water. The organic phasewas dried with anhydrous sodium sulfate and the solvent was evaporated.The final yellow oil was purified with a silica gel column.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.89 (t, 2H), 3.6 (t, 2H),4.6 (s, 2H), 7.2-7.4 (m, 5H)

Experimental: Section 16

Bis(trithiopropionic acid) (0.275 mmol) was dissolved in THF (4 mL) anddegassed for 15 minutes. Recrystallized azobisisobutyronitrile (AIBN)(0.55 mmol) was added to a round bottom flask and attached to acondenser. The mixture was stirred at 80° C. overnight.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.85 (s, 6H), 2.8 (t, 2H),3.0 (t, 2H)

Experimental: Section 17

2-(((benzylthio)carbonothioyl)thio)acetic acid (BTCTPA) (3.67 mmol) wasadded to a round bottom flask and dissolved in DCM (30 mL). Diethylhydroxy phosphate (0.48 mL, 3.34 mmol) was added followed by DMAP (0.67mmol). In a separate vial DCC (3.67 mmol) was dissolved in DCM (6 mL)and the solution was added drop-wise under stirring in an ice bath. Theflask was flushed with Nitrogen and stirred for 28 hours at ambienttemperature.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 1.35 (t, 6H), 2.85 (t, 2H),3.6 (t, 2H), 4.2 (q, 4H), 4.4 (d, 2H), 4.6 (s, 2H), 7.2-7.4 (m, 5H)

Experimental: Section 18

(diethoxyphosphoryl)methyl 2-(((benzylthio)carbonothioyl)thio)acetate(BTCTPA-diethyl phosphate) (0.136 mmol) was added to DCM (3 mL). TMSBr(0.54 mL, 0.409 mmol) was added to the solution drop-wise under Nitrogenin an ice bath. The solution was stirred for 4 hours at ambienttemperature then rotovapped. Methanol (3 mL) was added and the solutionwas stirred for 1 hour. The solution was evaporated under vacuum andrecrystallized in 10% DCM/Hexane solution.

¹H NMR (300 MHz, CDCl₃), δ (ppm form TMS): 2.8 (t, 2H), 3.6 (t, 2H), 4.4(d, 2H) 4.6 (s, 2H), 7.2-7.4 (m, 5H)

These and other modifications and variations to the present inventionmay be practiced by those of ordinary skill in the art, withoutdeparting from the spirit and scope of the present invention, which ismore particularly set forth in the appended claims. In addition, itshould be understood the aspects of the various embodiments may beinterchanged both in whole or in part. Furthermore, those of ordinaryskill in the art will appreciate that the foregoing description is byway of example only, and is not intended to limit the invention sofurther described in the appended claims.

What is claimed:
 1. An intermediate compound for forming a RAFT agent,the intermediate compound having the formula:

where n is an integer from 1 to 20; m is an integer from 0 to 20; R₁ isH, an alkyl group, or a cyano group; R₂ is H, an alkyl group, or a cyanogroup; Y is OH, COOH, or NH₂; and X is OH, COOH, NH₂, a nitrobenzyl,benzyl, or para-methyl benzyl group.
 2. The intermediate compound ofclaim 1, wherein n is 2 to 10, and wherein Y is COOH.
 3. Theintermediate compound of claim 1, wherein R₁ is a methyl group, andwherein R₂ is a methyl group.
 4. The intermediate compound of claim 1,wherein m is 2 to 10, and wherein X is OH.
 5. The intermediate compoundof claim 1, wherein the intermediate compound has the formula:


6. The intermediate compound of claim 1, wherein m is
 0. 7. Theintermediate compound of claim 1, wherein X is a benzyl ring.
 8. Theintermediate compound of claim 1, wherein the intermediate compound hasthe formula:


9. A salt of the intermediate compound of claim
 1. 10. A RAFT agentcomprising a thiocarbonylthio-containing organic compound having aphosphonic end group.
 11. The RAFT agent as in claim 10, wherein thephosphonic end group is a phosphonic acid group.
 12. The RAFT agent asin claim 10, having the formula:

where Z is an organic linkage; R₁ is H or an alkyl group; R₂ is H or analkyl group; A is O, S, or NH; and R″ is an organic end group.
 13. TheRAFT agent as in claim 12, wherein R″ comprises an alkyl groupterminating with a phenyl end group or a nitrophenyl end group.
 14. TheRAFT agent as in claim 13, wherein R″ comprises a benzyl group, anitrobenzyl group, or a para-methyl benzyl group.
 15. The RAFT agent asin claim 12, wherein R₁ is H or an alkyl group having a formula ofC_(n)H_(2n+1), with n being an integer of 1 to
 6. 16. The RAFT agent asclaim 12, wherein R₁ is a methyl group, an ethyl group, a propyl group,an iso-propyl group; a butyl group, or a tert-butyl group.
 17. The RAFTagent as claim 12, wherein R₂ is H or an alkyl group having a formula ofC_(n)H_(2n+1), with n being an integer of 1 to
 6. 18. The RAFT agent asin claim 12, wherein R₂ is a methyl group, an ethyl group, a propylgroup, an iso-propyl group; a butyl group, or a tert-butyl group. 19.The RAFT agent as in claim 12, wherein the organic linkage of Zcomprises an ester group or an ethyl acetate linkage.
 20. The RAFT agentas in claim 12 having the formula:

where n is 1 to 10, m is 1 to 10, R₁ is H or an alkyl group; R₂ is H oran alkyl group; A is O, S, or NH; and R″ is an organic end group. 21.The RAFT agent as in claim 12, wherein R″ is a benzyl group.
 22. TheRAFT agent as in claim 21, wherein a nitro group is positioned on thebenzyl group.
 23. The RAFT agent as in claim 22, wherein the nitro groupis positioned on the benzyl group at the para position.
 24. The RAFTagent as in claim 12, wherein A is O, NH, or S.
 25. The RAFT agent as inclaim 12, wherein the RAFT agent is selected from the group consistingof:


26. A salt of the RAFT agent of claim
 12. 27. A method of forming apolymer chain on a surface of a nanoparticle, the method comprising:attaching the RAFT agent of claim 10 to the surface of the nanoparticle,wherein the phosphonic group of the RAFT agent is covalently bonded tothe surface of the nanoparticle; and attaching a polymer to the RAFTagent.